DK153756B - METHOD FOR PREPARING 6-DEMETHYL-6-DESOXY-6-METHYLENE-5-HYDROXYTETRACYCLINE BY 11A-DEHALOGENATION OF 11A-CHLOR OR 11A-BROMO-6-DEMETHYLETHYL-6-DESOXYL-6-DESOXYL - Google Patents

Description

in

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This invention relates to a particular process for the preparation of 6-demethyl-6-deoxy-6-methylene-5-hydroxy-tetra-cyclin by reacting 11a-chloro or 11a-bromo-6-demethyl-6-deoxy-6- methylene-5-hydroxytetracycline in amphoteric form or base form or as an acid addition salt thereof in a reaction inert solvent with a dehalogenating agent.

11α-halo-6-demethyl-6-deoxy-6-methylene-5-hydroxy-tetracyclines, which for convenience are referred to herein as 10α-halo-6-methylene-5-hydroxy-tetracyclines, are important intermediates for the synthesis of the valuable and widespread antibiotic 6-demethyl-6-deoxy-6-methyl-5-hydroxytetracycline.

The known methods for 11a dehalogenation of 11α-15 halogen tetracyclines, including 11α-halogen-6-methylene tetracyclines are disclosed in U.S. Patent No. 3,043,875.

These methods include a variety of reactions, such as treatment of the IIa-halogen tetracyclines: (a) with dilute aqueous hydrogen iodide acid, (b) with zinc metal in the presence of a proton donor such as acetic acid, (c) in the case of IIa-bromo and IIa iodine compounds, by boiling the product with a solvent capable of reacting with bromine or iodine (acetone, methanol, etc.); (d) alternatively with sodium iodide in an organic solvent, followed by treatment of the resulting iodine compound with metallic zinc, (e) with metal sulfites and hydrogen sulfites, in particular the alkali metal salts (Na, K, Li) are useful, and (f) by catalytic hydrogenation in a reaction inert

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2 medium with hydrogen gas in the presence of a precious metal catalyst.

A further procedure, described in FR Patent No. 2 136 138, consists in electrochemical dehalogenation.

The dehalogenation of α-halogenic compounds, for example ketones and nitriles, by tertiary phosphines has been reported by Borowitz et al., Tetrahedron Letters, no. 11, 471-4 (1962), Partos et al., 0. Am.

Chem. Soc. 87, 5068-75 (1965) and Borowitz et al., J.

10 Org. Chem. 33, 3686-90 (1968). The use of diphenylphosphine, a secondary phosphine, as a dehalogenating agent for α-halogen ketones is described by Borowitz et al., J. Org. Chem. 34, 2687-92 (1969). Triethylphosphite has been shown to act as a dehalogenating agent by Pudovik et al., Zhur. Obschei Khim. 28, 1496-1500 (1958), (C.A. 53, 216 g) and Kreutzkamp et al., Ann.

609, 39 (1957).

The known methods for 11a dehalogenation of 11a-halogen tetracyclines suffer from disadvantages arising from the use of expensive catalysts (method f) or expensive equipment (electrochemical dehalogenation), reaction mixtures which are often difficult to separate due to by-products, and frequently incomplete conversion to the 11a dehalogenated product.

25. It has now been found that 11a-chloro and 11a-bromo-6-methylene-5-hydroxytetracycline can be dehalogenated readily and without the aforementioned disadvantages to form 6-methylene-5-hydroxytetracycline in good yield in the process. according to the invention, characterized in that at least one equimolar amount of tri (n-butyl) phosphine, triphenylphosphine, tris- (4-methoxyphenyl) phosphine, dimethylphenylphosphine, diphenylphosphine, diphenylphosphine,

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3 phosphine or triethyl phosphite.

The IIa-halo-6-methylene-5-hydroxtetracyclines used as starting materials have the formula: 3H2 OH N (CHg) 2 -conh2 wherein Z means chlorine or bromine, or are acid addition salts thereof.

Particular interest is enjoyed by the IIa-chloro compound because it is easier to manufacture and because of its stability over the corresponding IIa-bromine compound is readily isolated and stored without degradation.

In the process of the invention, an 11α-halogen-6-methylene-5-hydroxytetracycline of the above formula is treated in amphoteric or base form or as an acid addition salt thereof in a reaction inert solvent with one of the dehalogenating agents specified in the claim. Suitable solvents are hydroxyl-containing solvents such as water, alkanoic acids and substituted alkanoic acids wherein the substituent is selected from lower alkoxy, hydroxy and cyano, alcohols and substituted alcohols, wherein the substituent is selected from hydroxy and lower alkoxy. Preferred solvents are water, methanol, ethanol and mixtures thereof. Further, mixtures of such hydroxyl-containing solutions may be used

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solvents with non-hydroxyl-containing solvents, such as lower alkyl esters of lower alkanoic acids (methyl acetate, ethyl acetate, methyl propionate), tetrahydrofuran, dioxane, aromatic hydrocarbons (e.g. benzene, toluene, xylene), ketones (e.g. acetone and methylisobutyl ketone), and di (lower-alkyl) alkanoic acid amides (e.g., N, N-dimethylformamide and N, N-dimethylacetamide).

The reaction temperature is not critical. The reaction can take place over a wide temperature range, e.g. from 20 ° C 10 to the boiling point of the solvent system. Lower temperatures can be used but are not advantageous since the reaction is found to be relatively slow at lower temperatures. The most appropriate reaction temperature is room temperature, ie. 20-30 ° C. Higher temperatures, of course, have the advantage of speeding up the reaction and the disadvantage, although relatively small, of requiring greater caution when working on a large scale when using volatile solvents. When triethylphosphite is used as a dehalogenating agent, the reaction can take place at temperatures from 50 ° C to the boiling point of the solvent system. The reaction is so slow at below 50 ° C that it is not practical.

The 1α-halo-6-methylene-5-hydroxytetracycline reactants can be used in amphoteric or base form or as an acid addition salt. In practice, they are commonly used as acid addition salts as this is the form in which they are usually isolated. The nature of the acid addition salt is generally irrelevant to the reaction. The hydrochloride and p-toluenesulfonate salts are the salt forms in which the 30 IIa-halo-6-methylene-5-hydroxytetracyclines are generally isolated, especially on large scale preparations, and are therefore the form in which they are commonly used.

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The 5α-halo-6-methylene-5-hydroxytetracycline does not need to be completely dissolved in the dissolution medium used. The reaction takes place satisfactorily in mixtures in which it is only partially soluble.

The 5α-halo-6-methylene-5-hydroxytetracycline reactant and the dehalogenating agent are usually reacted in a molar ratio of 1: 1 to 1: 3. The preferred molar ratio of the 11a-halogen-6-methylene-5-hydroxy-tetracycline compound to the dehalogenating agent is 10 from 1: 1 to 1: 1.5. Higher ratios can be used but serve no useful purpose.

The products are isolated by methods commonly used to isolate 6-methylenetetracyclines, such as extraction and precipitation. The dehalogenating agents and the products to which they are converted do not appear to damage the insulation procedures.

The process according to the invention is further illustrated by the following examples.

Example 1 6-Demethyl-6-deoxy-6-methylene-5-hydroxytetracycline p-toluenesulfonate A. To a stirred solution of 6.4295 g (10 mmol) of 11α-chloro-6-demethyl-6-deoxy-6 -Methylene-5-hydroxytetracycline-p-toluenesulfonate in 12 ml of N, N-dimethylformamide and 7 ml of benzene at room temperature is added 3.9343 g (15 mmol) of triphenylphosphine. The mixture becomes warm and heated. to 90 ° C for 50 minutes. It is then cooled and poured into 375 ml of benzene. The yellow solid which is precipitated is isolated by filtration, washed with diethyl ether and air dried to give 4.275 g (70.6%) of the

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6 bothered product. It is identified by NMR spectroscopy as 6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline with the known properties of this compound.

The filtrate and wash solutions are combined, washed successively with water (2 x 100 ml) and brine (1 x 50 ml) and dried with anhydrous sodium sulfate. Removal of the solvent gives a brownish residue (3.306 g).

The residue is dissolved in chloroform and chromatographed on a silica gel column. Elution with chloroform followed by 10 of 15% ethyl acetate in chloroform and evaporation of the eluate gives triphenylphosphine oxide in 93% yield.

(Mp: 155 - 157 ° C).

On the basis of the yield of recovered triphenylphosphine oxide, the conversion of the 11a-chloro compound to the des-chloro analog is also at least 93%. The fact that less than 93% yield of the 11a-deshalo gene analogue is isolated must be attributed to incomplete precipitation of the product with benzene.

Example 2 6-Demethyl-6-deoxy-6-methylene-5-hydroxytetracycline sulfosalicyte A. A methanol solution of 0.62 ml (5 mmol) of tri (n-butyl) phosphine is added at room temperature to a solution of 1.536 g (3.1 mmol) 11a-chloro-6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline hydrochloride in 15 ml of methanol and the mixture is stirred for 20 hours. One third of the reaction mixture is treated with a solution of sulfosalicylic acid (1 ml, 1 M aqueous solution), the mixture is stirred for 15 minutes and then filtered to recover 0.424 g (61%) of the above compound, identified by ultraviolet, infrared and NMR spectrometer

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7 copy with known properties of this compound.

The filtrate is evaporated under reduced pressure and the residue partitioned between water and chloroform. The aqueous phase is separated, extracted with chloroform (2 x 10 ml), decolorized and the combined extracts are dried, dried over sodium sulfate and evaporated under reduced pressure. The residue, a viscous oil, crystallized by storage in a high vacuum (0.135 g, 62% yield). The mass spectrum showed that it consisted of tri (n-butyl) phosphine oxide.

Example 3 6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline hydrochloride

The remaining two thirds of the reaction mixture of Example 2, on standing, separated for 3 days a yellow solid. The solid is filtered off, washed with benzene and air dried to give (0.658g, 69% yield) of the above compound, identified by thin layer chromatography in the tetrahydrofuran / water (95: 5) system on silica gel plate at pH 6.0, where it showed a Rf 20 of 0.5.

Example 4 6-Demethyl-6-deoxy-6-methylene-5-hydroxytetracycline sulphosalicylate A. To a solution of 2.052 g (4.0 mmol) of 11a-chloro-6-demethyl-6-deoxy-6- methylene-5-hydroxytetracycline hydrochloride in 10 ml of acetone and 2 ml of water at room temperature is added 1.61 g (4.2 mmol) of tris- (4-methoxyphenyl) -phosphine over 5 minutes. A slight exothermic reaction occurs and a water bath is used to maintain temp.

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8 at room temperature. After stirring for 1 hour, the reaction mixture is concentrated under reduced pressure to remove the acetone. 20 ml of methanol is added followed by 15 ml of a 10% methanolic solution of sulfosalicylic acid. The mixture is stirred for 4 hours and then cooled to about 15 ° C. The solid product is filtered off, washed with cold methanol (2x5 ml) and dried in vacuo to give 2.54 g (96.2%) of the above product. It is identical to the product of Example 3.

Example 5 6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline hydrochloride

By repeating the procedure of Example 4-A, but using 4.2 mmol of dimethylphenylphosphine instead of tris- (4-methoxyphenyl) -phosphine, 1,598 g (84µ) of the above product having the known properties of this compound is obtained.

Example 6 6-Demethyl-6-deoxy-6-methylene-5-hydroxytetracycline sulfosalicylate (In triethylphosphite dehalogenation)

A mixture of 3.82 g (23.0 mmol) of triethyl phosphite and 3.214 g, (4.51 mmol) of 11a-chloro-6-demethyl-6-deoxy-6-25 methylene-5-hydroxytetracycline p-toluenesulfonate in 34 ml of ethanol is heated to reflux for 1 hour. It is then cooled to room temperature and stirred for 3 hours, then cooled to 0 ° C and the precipitated solid is isolated by filtration. The filtrate is treated with

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9 20 ml of a 10% aqueous solution of sulfosalicylic acid and stirred at room temperature overnight. The product is recovered by filtration, quenched with cold methanol and dried in vacuo to give 2.163 g (73%) of the above product.

An additional 0.148 g of product is recovered from the filtrate by removing the alcohol. (Total yield: 2.311 g, 78%). The product is identified by its ultraviolet, infrared and NMR spectra and exhibits the known properties of this compound.

Example 7 6-Demethyl-6-deoxy-6-methylene-5-hydroxytetracycline sulphosalicylate

A mixture of 2.927 g (4.31 mmol) of 11a-chloro-6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline-p-toluenesulfonate, 30 ml of methanol, 4 ml of water and 1.205 g (4, (60 mmol) triphenylphosphine is stirred under an atmosphere of nitrogen at room temperature for 3 hours. 18 ml of methanol and 20 ml of a 10% aqueous solution of sulfosalicylic acid are added, 20 and the mixture is stirred thoroughly and allowed to crystallize on standing for 18 hours. The product is filtered off, washed with cold methanol (0-5 ° C) and dried to give 2.671 g of the above product, 88% yield, with the known properties of this compound.

Example 8 27.21 mg (0.1575 mmol) of diphenylphosphine is added to a solution of 25.7 mg (0.050 mmol) of 11a-chloro-6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline hydrochloride in 1 , 5 ml of methanol under an atmosphere of nitrogen. The mixture is stirred for 28 hours and then evaporated to dryness

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10 in vacuo. The oily residue is washed with ether (3 x 1 ml) and then dissolved in methanol (0.32 ml). 0.16 ml of a 10% aqueous solution of sulfosalicylic acid is added and the mixture is stirred overnight. The mixture is heated 3 to 38-40 ° C and the liquid phase is evaporated to about 0.5 ml by exposing the hot mixture to a stream of nitrogen gas. Then it is centrifuged and the liquid is drained off and the crystals are washed with ether (1 ml). The supernatant is then passed through a column of "Amberlite® IR-45" 10 (hydroxide form of a weakly basic anion exchange resin), which has already been slurried in 1N methanolic hydrogen chloride, packed in a column and rinsed thoroughly with methanol. The eluate is collected and evaporated to dryness in vacuo. The residue is taken up in the minimum volume of ethanol and the solution is evaporated under reduced pressure to completely dry the product. Yield = 15 mg, 45.4%, 6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline as free base.

UV Λ mgx (CH 2 OH / 0.01 N HCl): 253 and 345 nm, log δ: 4.37 and 4.19.

The 1 H NMR spectrum of CF 2 COOH shows C-5 H at 4.8 ppm, the six N (CH 2) 2 protons at 3.3 ppm and the two C-6 = CH 5.7 ppm.

Claims (1)

V GB 153756 B Process for the preparation of 6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline by reaction of 11a-chloro or 11a-bromo-6-demethyl-6-deoxy-6-methylene-5 hydroxytetracycline in amphoteric or base form or as an acid addition salt thereof in a reaction inert solvent with a dehalogenating agent, characterized in that at least one equimolar amount of tri (n-butyl) phos-phine, triphenylphosphine, tris- methoxyphenyl) phosphine, dimethylphenylphosphine, diphenylphosphine or triethylphosphite.